Masterstudiengang "Drug Regulatory Affairs"


A Step Beyond Module 3 of Biodegradable Implants ***

Tanja Weber (Abschlußjahr: 2007)


The aim of this master thesis is to provide information about special contents of module 3 for biodegradable implants, to impart basic understanding for this modern dosage form and to outline regulatory aspects in order to ease and accelerate the process of dossier generation. The focus is on monolithic implants with a polymer matrix consisting of lactic and glycolic acid.
Regulatory affairs managers for the first time dealing with such implants can use this thesis as an overview and guide through this complex topic. The most important characteristics and challenges related to general aspects of pharmaceutical development, manufacturing and analysis are identified and evaluated. The following topics are highlighted:

Manufacturing process
This section presents the main principles of melt-extrusion together with a description of the necessary equipment, the control parameters and the underlying production steps. It discusses the possible influences on the final product quality such as the drug substance characteristics in the embedding matrix.

Sterilisation process
Manufacturing under clean room conditions with subsequent gamma radiation of the final product is a common procedure for biodegradable implants. This sterilisation method, including the derivation of the minimum and maximum absorbed radiation dose, is justified. In addition, this section presents the requirements for a proper process description, specification and validation as well as the effects on the final product quality like the polymers molecular weight distribution or the drug release behaviour.

Drug release and in vitro testing
The first part of this chapter explains the release characteristics together with the basic mechanisms of surface and bulk erosion. The second describes the in vitro release testing by using a modified flow-through cell under accelerated conditions without concealing the limited significance for the in vivo performance.

Control of the polymer matrix
The most widely investigated polymers in view of biocompatibility are the aliphatic polyesters based on lactic and glycolic acid. This section verifies their safety and summarises the requirements for biocompatibility and quality control.

Size-exclusion chromatography
Pressure-driven SEC is a commonly used, relative method to determine molar masses and distributions of synthetic and biological polymers. It requires calibration with suitable standards in order to achieve reliable results. This chapter presents the general principles and challenges of the SEC-technique and defines its analytical results, i.e. polydispersity index, number- and weight-average molecular weight.

Final product specifications
This section discusses some particularities of implants concerning the specified parameters drug release testing, assay determination, weight-average molecular weight of the polymer matrix and functionality of the syringe.

Container closure system
The syringe and the sachet are the primary packaging of the medicinal product. The first part of this section describes the construction of an exemplary syringe system and the underlying mode of operation. The second deals with the qualification of the used plastic materials. It is necessary to prove the integrity of the packaging after gamma-irradiation which can lead to chain scission and cross-linking phenomena.

This part gives an overview of possible test parameters for the stability program of biodegradable implants. The latter must be able to cover all relevant factors with an influence on the shelf-life such as the heat sensitivity of the polymer matrix, the stability of the drug substance, possible interactions between API and matrix including the formation of impurities as well as the long-term effects of gamma-irradiation.

Pages: 69